Three-dimensional resorbable implants for tissue reinforcement and hernia repair

ABSTRACT

Resorbable three-dimensional implants that can be temporarily deformed, implanted by minimally invasive means, and resume their original shape in vivo, have been developed. These implants are particularly suitable for use in minimally invasive procedures for tissue reinforcement, repair of hernias, and applications where it is desirable for the implant to contour in vivo to an anatomical shape, such as the inguinofemoral region. In the preferred embodiment, the implants are made from meshes of poly-4-hydroxybutyrate monofilament that have reinforced outlying borders that allow the meshes to form three-dimensional shapes that can be temporarily deformed. These implants can resume three-dimensional shapes after being temporarily deformed that contour to the host&#39;s tissue or an anatomical shape, for example, in the repair of a hernia, and particularly a hernia in the inguinofemoral region. The implants can contour to the host&#39;s tissue for example, of the inguinofemoral region, without the implants wrinkling, bunching or folding.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Ser. No. 61/986,499, filed onApr. 30, 2014, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to resorbable polymericcompositions that can be processed into fibers, converted into textileconstructs such as knitted and woven meshes, and subsequently formedinto three-dimensional shapes suitable for tissue reinforcement andhernia repair. The three-dimensional shapes may be temporarily deformedto allow their implantation by minimally invasive methods, and will thenresume their original three-dimensional shape. The polymericcompositions include resorbable polyhydroxyalkanoates (PHA) polymers andcopolymers, including poly-4-hydroxybutyrate and copolymers thereof.

BACKGROUND OF THE INVENTION

Mesh products made from non-resorbable fibers, such as polypropylene andpolyester, are well known in the prior art, and widely used in herniarepair. Non-resorbable curved polypropylene meshes that can assume acurved shape are also now commonly used in hernia repair particularlyfor reinforcement of the inguinofemoral region. For example, U.S. Pat.Nos. 5,954,767, 6,368,541, 6,723,133 and 6,740,122 to Pajotin disclosecurved knitted non-resorbable polypropylene meshes for repairing defectsin muscle or tissue walls.

More recently, hernia repair products made from poly-4-hydroxybutyrate(P4HB) resorbable fibers have been disclosed by Martin et al. J. Surg.Res. 184:766-773 (2013), and are now used in the clinic. However, theseresorbable products are either flat meshes or hernia repair plugs, andare not curved shapes that can be temporarily deformed, implanted, andreleased in vivo so that they conform to the anatomical shape, forexample, of the inguinofemoral region.

There is thus a need to develop three-dimensional resorbable implantsthat can be temporarily deformed, implanted by minimally invasivemethods, and that will resume their original three-dimensional shapeafter implantation, which also have the mechanical and physicalproperties suitable for use in plastic surgery and reconstruction.

It is an object of the present invention to provide resorbablethree-dimensional implants that can be temporarily deformed, implantedby minimally invasive methods, and resume their originalthree-dimensional shape after implantation and contour to an anatomicalshape.

It is a further object of the present invention to provide processes toproduce resorbable three-dimensional implants that can be temporarilydeformed from polyhydroxyalkanoate (PHA) and other resorbable polymers.

It is another object of the present invention to provide resorbablethree-dimensional PHA implants that can be temporarily deformed that aremade from monofilament and/or multifilament fibers of 4-hydroxybutyratemonomers or other resorbable polymeric monomers.

It is yet another object of the invention to provide resorbablethree-dimensional implants, that can be temporarily deformed, and thatare made from P4HB monofilament and/or multifilament meshes.

It is still another object of the invention to provide resorbablethree-dimensional implants for use in tissue reinforcement and herniarepair that can be temporarily deformed, implanted by minimally invasivemeans, and resume their original shape in vivo and are designed tocontour to the patient's host tissue or an anatomical shape.

It is still a further object of the invention to provide methods toimplant resorbable three-dimensional implants that can be temporarilydeformed to allow for minimally invasive delivery.

SUMMARY OF THE INVENTION

Resorbable three-dimensional implants that can be temporarily deformed,implanted by minimally invasive means, and resume their original shapein vivo, have been developed. These implants are particularly suitablefor use in minimally invasive procedures for tissue reinforcement, therepair of hernias, and applications where it is desirable for theimplant to contour in vivo to an anatomical shape, such as theinguinofemoral region. In the preferred embodiment, the implants aremade from meshes of poly-4-hydroxybutyrate monofilament that havereinforced outlying borders that allow the meshes to formthree-dimensional shapes that can be temporarily deformed. Theseimplants can resume three-dimensional shapes after being temporarilydeformed that contour to the host's tissue or an anatomical shape, forexample, in the repair of a hernia, and particularly a hernia in theinguinofemoral region. The implants can contour to the host's tissue forexample, of the inguinofemoral region, without the implants wrinkling,bunching or folding.

P4HB monofilament meshes can be molded into three-dimensional shapesthat can be temporarily deformed, and will resume their originalthree-dimensional shape provided the outlying border of thethree-dimensional shape has been reinforced. In a preferred embodiment,the outlying border is reinforced using a ring of unoriented P4HB fiberextrudate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of a split metal form, consisting of an inwardlycurving half and a mating outwardly curving half with a semicirculargroove in the outlying border of the inwardly curving half, which isused to make resorbable implants that can assume a three-dimensionalshape unaided. A line in the outwardly curving half designated by theletters “AA” denotes the position of a cross-section with an arrowpointing at a separate view of the cross-section.

DETAILED DESCRIPTION OF THE INVENTION

Methods have been developed to prepare resorbable three-dimensionalimplants, from monofilament mesh, that can be temporarily deformed toallow implantation by minimally invasive methods. After implantation,the three-dimensional implants resume their original shape unaided, andcan be designed so that they contour to the anatomical shape of thebody. The resorbable three-dimensional implants are particularly usefulwhen it is desirable for the implant to contour to the anatomical shapeof the body without bunching, folding or wrinkling. For example,placement of a flat mesh in the inguinofemoral region to repair a herniacan result in a flat mesh wrinkling and slipping out of position. Incontrast, a three-dimensional mesh can be designed to contour to thehost's tissue, and even stay in place without the need for fixation.

The resorbable implants are preferably made from PHA polymers, and morepreferably polymers of 4-hydroxybutyrate, and even more preferably fromP4HB. Meshes made from monofilament and/or multifilament fibers of PHAs,such as 4HB, however have very different properties from meshes madefrom polypropylene fibers. Therefore methods that have been used, forexample by Pajotin as disclosed in U.S. Pat. Nos. 5,954,767, 6,368,541,6,723,133 and 6,740,122 are not adequate to create P4HBthree-dimensional implants that can be temporarily deformed, implantedby a minimally invasive method, and are able to resume their originalshape. This is primarily because polypropylene fibers are significantlystiffer than P4HB fibers, and have a lower elongation to break. Thus amesh of polypropylene monofilament fibers can be molded into athree-dimensional shape, temporarily deformed, and upon release willresume its original three-dimensional shape. In contrast, when a mesh ofP4HB fibers is molded into a three-dimensional shape and temporarilydeformed, it will not resume its original three-dimensional shape.

The methods disclosed herein are based upon the discovery that P4HBmonofilament meshes can be molded into three-dimensional shapes that canbe temporarily deformed, and will resume their originalthree-dimensional shape provided the outlying border of thethree-dimensional shape has been reinforced. In a preferred embodiment,the outlying border is reinforced using a ring of unoriented P4HB fiberextrudate.

I. Definitions

“Bioactive agent” is used herein to refer to therapeutic, prophylactic,and/or diagnostic agents. These include physiologically orpharmacologically active substances that act locally or systemically inthe body. A biologically active agent is a substance used for, forexample, the treatment, prevention, diagnosis, cure, or mitigation ofone or more symptoms or characteristics of a disease or disorder, asubstance that affects the structure or function of the body, orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment. Bioactiveagents include biologically, physiologically, or pharmacologicallyactive substances that act locally or systemically in the human oranimal body. Examples can include, but are not limited to,small-molecule drugs, peptides, proteins, sugars, polysaccharides,nucleotides, oligonucleotides, and nucleic acids molecules such asaptamers, siRNA, miRNA and combinations thereof.

“Biocompatible” as generally used herein means the biological responseto the material or device is appropriate for the device's intendedapplication in vivo. Metabolites of these materials should also bebiocompatible.

“Blend” as generally used herein means a physical combination ofdifferent polymers, as opposed to a copolymer comprised of two or moredifferent monomers.

“Burst strength” as used herein is determined by test method ASTMD6797-02 “Standard test method for bursting strength of fabrics constantrate of extension (CRE) ball burst test,” using a MTS Q-Test Eliteuniversal testing machine or similar device. The testing fixture uses a⅜ inch diameter ball.

“Copolymers of poly-4-hydroxybutyrate” as generally used herein meansany polymer which includes 4-hydroxybutyrate with one or more differenthydroxyalkanoic acid units.

“Elongation” or “extensibility” of a material means the amount ofincrease in length resulting from, as an example, the tension to break aspecimen. It is expressed usually as a percentage of the originallength. (Rosato's Plastics Encyclopedia and Dictionary, Oxford Univ.Press, 1993).

“Molecular weight” as used herein, unless otherwise specified, refers tothe weight average molecular weight (Mw), not number average molecularweight (Mn), and is measured by gel permeation chromatography (GPC)relative to polystyrene.

“Polyhydroxyalkanoates” or “PHAs” are linear polyesters produced bybacterial fermentation. Depending upon the microorganism and thecultivation conditions, homo- or copolyesters with differenthydroxyalkanoic acids are generated.

“Poly-4-hydroxybutyrate” as generally used herein means a homopolymer of4-hydroxybutyrate units. It may be referred to herein as P4HB orTephaFLEX® biomaterial (manufactured by Tepha, Inc., Lexington, Mass.).Polyhydroxybutyrate as generally used in the literature refers to thenaturally occurring polymer poly-3-hydroxybutyrate.

“Reinforced” refers to a device formed of a material such as a P4HM thatcannot be deformed and resume its pre-deformation shape, which containsa fiber, fibers, or region which causes the device to resume itspre-deformation shape following deformation. Examples of reinforcingmaterials are described below. These may be made of the same ordifferent materials, wherein the reinforcement is caused by thecomposition or physical shape (suture, braid, weaving) of thereinforcing material.

“Resorbable” as generally used herein means the material is broken downin the body and eventually eliminated from the body. The terms“resorbable”, “degradable”, “erodible”, and “absorbable” are usedsomewhat interchangeably in the literature in the field, with or withoutthe prefix “bio”. Herein, these terms will be used interchangeably todescribe material broken down and gradually absorbed or eliminated bythe body within five years, whether degradation is due mainly tohydrolysis or mediated by metabolic processes.

“Suture pullout strength” as used herein means the peak load (kg) atwhich an implant fails to retain a suture. It is determined using atensile testing machine by securing an implant in a horizontal holdingplate, threading a suture in a loop through the implant at a distance of1 cm from the edge of the implant, and securing the suture arms in afiber grip positioned above the implant. Testing is performed at acrosshead rate of 100 mm/min, and the peak load (kg) is recorded. Thesuture is selected so that the implant will fail before the suturefails. The suture pullout strength may be converted and expressed asNewtons.

“Taber Stiffness Unit” is defined as the bending moment of ⅕ of a gramapplied to a 1½″ (3.81 cm) wide specimen at a 5 centimeter test length,flexing it to an angle of 15°, and is measured using a Taber V-5Stiffness Tester Model 150-B or 150-E. The TABER® V-5 StiffnessTester—Model 150-B or 150-E is used to evaluate stiffness and resiliencyproperties of materials up to 10,000 Taber Stiffness Units. Thisprecision instrument provides accurate test measurement to ±1.0% forspecimens 0.004″ to 0.219″ thickness. One Taber Stiffness Unit is equalto 1 gram cm (g cm) or 0.0981 milliNewton meters (mN m). Taber StiffnessUnits can be converted to Genuine Gurley™ Stiffness Units with theequation: S_(T)=0.01419S_(G)−0.935, where S_(T) is the stiffness inTaber Stiffness Units and S_(G) is the stiffness in Gurley StiffnessUnits. To convert Taber Stiffness Units to milliNewton Meters, use theequation: X=S_(T)·0.098067, where X is the stiffness in milliNewtonMeters.

“Tensile modulus” is the ratio of stress to strain for a given materialwithin its proportional limit.

II. Compositions

Methods have been developed to produce three-dimensional shapes from PHAcompositions that can be temporarily deformed, and implanted using aminimally invasive method. After implantation, the three-dimensionalshapes will resume their original shapes. The three-dimensional shapesare designed to contour to a patient's anatomy, and in particular to theanatomy of the inguinofemoral region.

A. Polymers

The methods described herein can typically be used to producethree-dimensional shapes from polyhydroxyalkanoates polymers, and morepreferably from poly-4-hydroxybutyrate (P4HB) or a copolymer thereof.Copolymers include 4-hydroxybutyrate with 3-hydroxybutyrate, and4-hydroxybutyrate with glycolic acid monomer. P4HB and copolymersthereof can be obtained from Tepha, Inc. of Lexington, Mass. PreferredPHA polymers have a weight average molecular weight (Mw) of 50,000 to1,200,000, preferably 100,000 to 1,000,000 and more preferably, 100,000to 800,000 based on gel permeation chromatography (GPC) relative topolystyrene standards.

Polyhydroxyalkanaotes (PHAs) are produced by numerous microorganisms(see, for example, Steinbüchel A., et al. Diversity of BacterialPolyhydroxyalkanoic Acids, FEMS Microbial. Lett. 128:219-228 (1995)). Innature these polyesters are produced as storage granules inside cells,and serve to regulate energy metabolism. They are also of commercialinterest because of their thermoplastic properties, and relative ease ofproduction.

Poly-4-hydroxybutyrate (P4HB) and copolymers thereof can be producedusing transgenic fermentation methods, see, for example, U.S. Pat. No.6,548,569 to Williams et al., and are produced commercially, forexample, by Tepha, Inc. (Lexington, Mass.). P4HB is not naturallyoccurring. Poly-4-hydroxybutyrate (P4HB, TephaFLEX® biomaterial) is astrong, pliable thermoplastic polyester that, despite its biosyntheticroute, has a relatively simple structure. Chemical synthesis of P4HB hasbeen attempted, but it has been impossible to produce the polymer with asufficiently high molecular weight that is necessary for mostapplications, including melt processing (see Hori, Y., et al., Polymer36:4703-4705 (1995); Houk, K. N., et al., J. Org. Chem., 2008, 73 (7),2674-2678; and Moore, T., et al., Biomaterials 26:3771-3782 (2005)). Infact, it has been calculated to be thermodynamically impossible tochemically synthesize a high molecular weight homopolymer under normalconditions (Moore, T., et al., Biomaterials 26:3771-3782 (2005)).Chemical synthesis of P4HB instead yields short chain oily oligomersthat lack the desirable thermoplastic properties of the high molecularweight P4HB polymers produced by biosynthetic methods.

It should be noted that the literature commonly refers to anotherpolyhydroxyalkanoate, poly-3-hydroxybutyrate (P3HB), simply aspolyhydroxybutyrate (PHB) (see Section 2 of Moore, T., et al.,Biomaterials 26:3771-3782 (2005)). PHB has entirely different propertiesto P4HB. It is structurally and functionally different to P4HB. Forexample, PHB has a melting point of 180° C. versus a melting point ofabout 61° C. for P4HB. The polymers also have substantially differentglass transition temperatures and mechanical properties. For example,PHB is a relatively hard brittle polymer with an extension to break ofjust a few percent, whereas P4HB is a strong extensible polymer with anextension to break of about 1000%. Substantially different conditionsare required to process these two polymers, and the resulting productshave substantially different properties.

U.S. Pat. Nos. 6,245,537, 6,623,748, 7,244,442, and 8,231,889 describemethods of making PHAs with little to no endotoxin, which are suitablefor medical applications. U.S. Pat. Nos. 6,548,569, 6,838,493,6,867,247, 7,268,205, 7,179,883, 7,268,205, 7,553,923, 7,618,448 and7,641,825 and WO 2012/064526 describe use of PHAs to make medicaldevices. Copolymers of P4HB include 4-hydroxybutyrate copolymerized with3-hydroxybutyrate or glycolic acid (U.S. Pat. No. 8,039,237 to Martinand Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No.6,323,010 to Skraly et al.). Methods to control molecular weight of PHApolymers have been disclosed by U.S. Pat. No. 5,811,272 to Snell et al.

PHAs with controlled degradation and degradation in vivo of less thanone year are disclosed by U.S. Pat. Nos. 6,548,569, 6,610,764,6,828,357, 6,867,248, and 6,878,758 to Williams et al. and WO 99/32536to Martin et al. Applications of P4HB have been reviewed in Williams, S.F., et al., Polyesters, III, 4:91-127 (2002), Martin, D. et al. MedicalApplications of Poly-4-hydroxybutyrate: A Strong Flexible AbsorbableBiomaterial, Biochem. Eng. J. 16:97-105 (2003), and Williams, S. et al.Poly-4-hydroxybutyrate (P4HB): a new generation of resorbable medicaldevices for tissue repair and regeneration, Biomed. Tech. (Berl) ISSN(Online) 1862-278X, ISSN (Print) 0013-5585, DOI: 10.1515/bmt-2013-0009,2013. Medical devices and applications of P4HB have also been disclosedby WO 00/56376 to Williams et al. Several patents including U.S. Pat.Nos. 6,555,123, 6,585,994, and 7,025,980 to Williams and Martin describethe use of PHAs in tissue repair and engineering. WO 2007/092417 to Rizket al. discloses compositions of PLA (polylactic acid) toughened withP4HB suitable for medical applications.

WO 04/101002 to Martin, et al., U.S. Pat. No. 8,034,270 to Martin etal., U.S. Pat. No. 8,016,883 to Coleman et al., and 8,287,909 to Martinet al., WO 2011/119742 to Martin et al., WO 06/015276 to Rizk, and WO2011/159784 to Cahil et al. disclose fibers, non-wovens, and textilesmade by melt extrusion of P4HB. However, none of these disclosuresdescribe three-dimensional shapes that can be temporarily deformed,implanted using minimally invasive methods, and reopened to theiroriginal shapes to conform to anatomical structures. These disclosuresalso do not describe processes that would be adequate to form suchshapes that can be temporarily deformed, and reopen to their originalshapes unaided.

If desired, the PHA polymer may be blended with another PHA polymerprior to processing, or blended with a non-PHA material, including otherabsorbable biocompatible polymers, dyes and bioactive agents (such asdrug molecules or other therapeutic, prophylactic or diagnostic agents).Other absorbable biocompatible polymers in any form, including fibers,may also be incorporated into the three-dimensional shapes to formhybrid structures. Other absorbable biocompatible polymers, include, butare not limited to, poly(lactides); poly(glycolides);poly(lactide-co-glycolides); poly(lactic acid); poly(glycolic acid);poly(lactic acid-co-glycolic acids); polycaprolactones;poly(orthoesters); polyanhydrides; poly(phosphazenes); synthetically orbiologically prepared polyesters (including polyesters with one or moreof the following monomeric units: glycolic, lactic; trimethylenecarbonate, p-dioxanone, or ε-caprolactone);poly(lactide-co-caprolactones); polycarbonates; tyrosine polycarbonates;polyamides (including synthetic and natural polyamides, polypeptides,and poly(amino acids)); polyesteramides; poly(dioxanones); poly(alkylenealkylates); polyethers (such as polyethylene glycol, PEG, andpolyethylene oxide, PEO); polyvinyl pyrrolidones or PVP; polyurethanes;polyetheresters; polyacetals; polycyanoacrylates;poly(oxyethylene)/poly(oxypropylene) copolymers; polyacetals,polyketals; polyphosphates; (phosphorous-containing) polymers;polyphosphoesters; polyalkylene oxalates; polyalkylene succinates;poly(maleic acids); chitin; chitosan; modified chitosan; collagen; silk;biocompatible polysaccharides; biocompatible copolymers (including blockcopolymers or random copolymers); hydrophilic or water soluble polymers,such as polyethylene glycol, (PEG) or polyvinyl pyrrolidone (PVP), withblocks of other biocompatible or biodegradable polymers, for example,poly(lactide), poly(lactide-co-glycolide, or polycaprolcatone orcombinations thereof. In some embodiments the implant includeshyaluronic acid or derivative thereof, collagen, hydroxyapatite, orabsorbable polymer with one or more the following monomeric units:glycolic acid, lactic acid, trimethylene carbonate, p-dioxanone, andcaprolactone.

In one embodiment, the implants include one or more of the following:dye, medical marker, contrast agent, radiopaque marker, radioactivesubstance.

B. Additives

Certain additives may be incorporated into P4HB, copolymers and blendsthereof prior to converting these compositions into three-dimensionalstructures. Preferably, these additives are incorporated during thecompounding process to produce pellets that can be subsequentlyprocessed into fibers suitable for making the three-dimensional shapes.In another embodiment, the additives may be incorporated using asolution-based process. In a preferred embodiment, the additives arebiocompatible, and even more preferably the additives are bothbiocompatible and resorbable.

In one embodiment, the additives may be nucleating agents and/orplasticizers. These additives may be added in sufficient quantity toproduce the desired result. In general, these additives may be added inamounts of up to 20% by weight. Nucleating agents may be incorporated toincrease the rate of crystallization of the P4HB homopolymer, copolymeror blend. Such agents may be used to improve the mechanical propertiesof fibers and meshes, and to reduce cycle times. Preferred nucleatingagents include, but are not limited to, salts of organic acids such ascalcium citrate, polymers or oligomers of PHA polymers and copolymers,high melting polymers such as PGA, talc, micronized mica, calciumcarbonate, ammonium chloride, and aromatic amino acids such as tyrosineand phenylalanine.

Plasticizers that may be incorporated into the compositions include, butare not limited to, di-n-butyl maleate, methyl laureate, dibutylfumarate, di(2-ethylhexyl) (dioctyl) maleate, paraffin, dodecanol, oliveoil, soybean oil, polytetramethylene glycols, methyl oleate, n-propyloleate, tetrahydofurfuryl oleate, epoxidized linseed oil, 2-ethyl hexylepoxytallate, glycerol triacetate, methyl linoleate, dibutyl fumarate,methyl acetyl ricinoleate, acetyl tri(n-butyl) citrate, acetyl triethylcitrate, tri(n-butyl) citrate, triethyl citrate, bis(2-hydroxyethyl)dimerate, butyl ricinoleate, glyceryl tri-(acetyl ricinoleate), methylricinoleate, n-butyl acetyl rincinoleate, propylene glycol ricinoleate,diethyl succinate, diisobutyl adipate, dimethyl azelate, di(n-hexyl)azelate, tri-butyl phosphate, and mixtures thereof. Particularlypreferred plasticizers are citrate esters.

In another preferred embodiment, the additives are contrast agents,radiopaque markers and radioactive substances. These additives may alsobe incorporated into the P4HB homopolymer, copolymer or blend eitherbefore preparing fibers and meshes that are molded intothree-dimensional shapes or after they are prepared.

C. Bioactive Agents

If desired, the P4HB homopolymer and copolymers thereof used to make thethree-dimensional shapes may incorporate bioactive agents. Thesebioactive agents may be added during the formulation process, duringpelletization or blending, or may be added later to the fibers ormeshes.

In one embodiment, the bioactive agents, the P4HB polymer, copolymer, orblend, may be dissolved in a solvent or solvent system in order todisperse the bioactive agent in the P4HB polymer, copolymer or blend,and the solvent may then be removed by evaporation. Preferred solventsinclude methylene chloride, chloroform, tetrahydrofuran, acetone,dimethylformamide, and 1,4-dioxane.

Examples of bioactive agents that can be incorporated into the P4HBpolymer, copolymer, or blends thereof, include, but are not limited to,small-molecule drugs, anti-inflammatory agents, immunomodulatory agents,molecules that promote cell migration, molecules that promote or retardcell division, molecules that promote or retard cell proliferation anddifferentiation, molecules that stimulate phenotypic modification ofcells, molecules that promote or retard angiogenesis, molecules thatpromote or retard vascularization, molecules that promote or retardextracellular matrix disposition, signaling ligands, platelet richplasma, anesthetics, hormones, antibodies, growth factors, extracellularmatrix or components thereof (fibronectin, laminin, vitronectin),integrins, antibiotics, steroids, hydroxyapatite, silver particles,vitamins, non-steroidal anti-inflammatory drugs, chitosan andderivatives thereof, alginate and derivatives thereof, collagen,hyaluronic acid and derivatives thereof, allograft material, xenograftmaterial, and ceramics. Representative materials include proteins,peptides, sugars, polysaccharides, nucleotides, oligonucleotides,lipids, lipoproteins, nucleic acid molecules such as antisensemolecules, aptamers, siRNA, and combinations thereof.

III. Three-Dimensional PHA Implants and Methods of Manufacturing

A. Fibers for Making Three-Dimensional PHA Medical Devices

In a preferred embodiment, the three-dimensional shapes are formed ofP4HB monofilament meshes. The P4HB monofilament fibers used to makethese meshes may be prepared by melt extrusion or solution spinning. TheP4HB monofilament fibers are made by melt extrusion, for example, asdescribed by WO 2011/119742 to Martin et al. and U.S. Pat. No. 8,034,270to Martin et al.

The diameters of the P4HB monofilament fibers may range from 10 μm to 1mm, but more preferably have a diameter ranging from 50 μm to 600 μm,and even more preferably from 50 μm to 250 μm. In a preferredembodiment, the P4HB monofilament fibers are oriented. The exactmechanical properties of the fibers will depend upon the degree oforientation. In a particularly preferred embodiment, the oriented P4HBmonofilament fibers will have one or more of the following properties: atensile strength of at least 100 MPa, more preferably at least 300 MPa,and even more preferably at least 500 MPa; an elongation to break ofless than 500%, more preferably less than 300%, and even more preferablyless than 100%; a tensile modulus of at least 100 MPa, more preferablyat least 300 MPa, and even more preferably at least 500 MPa.

In another embodiment, the three-dimensional shapes comprise P4HBmultifilament fibers. P4HB multifilament fibers may be prepared by meltextrusion or solution spinning. In a preferred embodiment, the P4HBmultifilament fibers are made by melt extrusion, and may be prepared asdescribed by WO 2011/119742 to Martin et al. and U.S. Pat. No. 8,034,270to Martin et al. In an embodiment the P4HB multifilament fibers areprepared with a denier per filament (dpf) of less than 6, morepreferably less than 4, and even more preferably less than 3. In anotherembodiment, the multifilament fibers are prepared with a tenacity ofgreater than 2 gram/denier, and more preferably greater than 4gram/denier.

B. Methods of Making PHA Meshes

In a preferred embodiment, the three-dimensional shapes include P4HBmonofilament meshes. Suitable P4HB monofilament meshes may be made asdisclosed by WO 2011/119742 to Martin et al. and U.S. Pat. No. 8,034,270to Martin et al.

In an embodiment, the PHA meshes have one or more of the followingproperties: a suture pullout strength of at least 10 N, and morepreferably at least 20 N; a burst strength of at least 1 Kg, morepreferably at least 10 Kg, and even more preferably at least 20 Kg; porediameters that are at least 50 μm, more preferably at least 100 μm, andeven more preferably over 250 μm; and a Taber stiffness that is lessthan 100 Taber stiffness units, and more preferably less than 10 Taberstiffness units.

In a preferred embodiment, the PHA mesh is made from P4HB monofilamentfiber. In a more preferred embodiment, the P4HB monofilament mesh has aknitted or woven structure. A particularly preferred P4HB monofilamentmesh has substantially one or more of the following properties: a porediameter of approximately 500 μm, thickness of 0.5 mm, areal density ofapprox. 182 g/m², suture pullout strength of 5.6 kgf, and a burststrength of 24.5 Kg.

In another embodiment, the PHA meshes may comprise different sizedfibers or other non-PHA fibers, including PHA multifilament, and fibersmade from other absorbable or non absorbable biocompatible polymers andhybrid meshes.

C. Method of Coating PHA Meshes

In an embodiment, the PHA meshes may be coated with other substances,such as additives and bioactive agents. The coatings may range from athin coating on the surface of a PHA fiber to complete coverage orencapsulation of a PHA mesh. The additives and bioactive agents may beapplied directly or first suspended or dissolved in a carrier, such asanother polymer. In a preferred embodiment, the PHA meshes may be coatedwith collagen.

D. Fabrication of Three-Dimensional PHA Implants

PHA polymers and copolymers possess properties that are useful forpreparing three-dimensional implants that can be temporarily deformed tofacilitate minimally invasive delivery, and contour to the patient'stissues or be shaped into anatomical forms once delivered in vivo. Theseimplants may be used, for example, in hernia repair and tissuereinforcement. The disclosed structures of PHA polymers and copolymersallow the implants to be deformed and subsequently assumethree-dimensional shapes unaided. The three-dimensional implants may beplaced without the need for fixation, reducing cost, and eliminating thechance of nerve entrapment. In contrast, flat mesh must be fixated toprevent it from moving. Because the three-dimensional implants aredesigned for easy positioning by contouring to the patient's anatomy,excessive folding and wrinkling that can occur in placing flat implantsis eliminated. In a particularly preferred embodiment, thethree-dimensional implants are formed and shaped for the inguinalanatomy, and may be used for the laparoscopic repair of inguinalhernias.

In an embodiment, the three-dimensional PHA implants are prepared bymolding. In these processes, PHA polymer or copolymer textilestructures, such as P4HB monofilament meshes, are molded into athree-dimensional implant. In a preferred embodiment, three-dimensionalshapes are prepared by molding a monofilament mesh of a PHA polymer orcopolymer into a shape designed to contour to the host's tissue. In aparticularly preferred embodiment, the shape is designed for herniarepair. Such shapes include those with an outwardly curving exterior andinwardly curving interior, and optionally contain an outlying borderthat is reinforced by a continuous or interrupted ring that allows thescaffold to assume a three-dimensional shape unaided after beingtemporarily deformed. Shapes with outwardly curving exteriors andinwardly curving interiors may, for example, be prepared using a splitmetal form consisting of an inwardly curving half and a mating outwardlycurving half as shown in FIG. 1. One skilled in the art will understandthat the size and shape of the split metal form can be varied in orderto provide different three-dimensional shapes that contour to thespecific needs of a patient. In a preferred embodiment, the inwardlycurving half of the metal form contains a semicircular groove in theoutlying border that will accommodate a continuous or interrupted ringof filament, thread, strand, string, fiber, yarn, wire, film, tape,tube, fabric, felt, mesh, multifilament, monofilament, or fiberextrudate. In a particularly preferred embodiment the groove willaccommodate a monofilament, preferably a monofilament extrudate. Thesemicircular groove is cut into the outlying border of the inwardlycurving half such that the ring of material, for example, amonofilament, will protrude from the groove. In an alternativeembodiment, the groove may be cut into the outwardly curving halfinstead of the inwardly curving half. A three-dimensional shape with aninwardly curving interior, outwardly curving exterior, and reinforcedoutlying border is prepared by placing, for example, a monofilamentextrudate in the semicircular groove of the inwardly curving half sothat it forms a ring, draping a polymeric material such as amonofilament mesh over the inwardly curving half of the metal form,placing the mating outwardly curving half of the metal form over thepolymeric material, and clamping the two halves of the split metal formtogether to form a block. The block is then heated, cooled,disassembled, and the three-dimensional shape removed and trimmed asnecessary to form a smooth outlying border. In an embodiment, the blockis heated uniformly, preferably by heating with hot water or otherheating media, and cooled uniformly, preferably by cooling with ambienttemperature water. In a preferred embodiment, the three-dimensionalshape is made from a poly-4-hydroxybutyrate monofilament mesh, and apoly-4-hydroxybutyrate monofilament extrudate. The temperature of thehot water is set such that the ring is either pressed or melted into theoutlying border to reinforce the outlying border. When thethree-dimensional shape is made from poly-4-hydroxybutyrate, thetemperature of the hot water is set at approximately 56° C., and thepolymer construct is heated for approximately 5 minutes. It has beendiscovered that if a ring of polymer, derived, for example, from apoly-4-hydroxybutyrate monofilament extrudate, is used to reinforce theoutlying border of the poly-4-hydroxybutyrate mesh, the mesh will beable to assume a three-dimensional shape unaided after being temporarilydeformed. The ring may be melted into the mesh as described above, orwelded, using, for example, sonic welding, or otherwise attached to theformed mesh. However, if a ring is not used to reinforce the edge of thepoly-4-hydroxybutyrate material (such as a monofilament mesh), thepoly-4-hydroxybuyrate material will not be able to assume athree-dimensional shape unaided after being temporarily deformed.

Three-dimensional shapes that can be temporarily deformed may also beprepared from porous P4HB films instead of fibers. For example, P4HBfilms may be prepared by melt extrusion or solution spinning. Thesefilms may be oriented, and then drilled or fibrillated to produce meshlike P4HB porous film structures. The latter may be reinforced by acontinuous or interrupted ring of filament, thread, strand, string,fiber, yarn, wire, film, tape, tube, fabric, felt, mesh, multifilament,monofilament, or fiber extrudate, so that they will assume athree-dimensional shape that can be temporarily deformed.

In an embodiment, the three-dimensional implants can incorporate one ormore tabs or straps (attachment sites) to accommodate suture throws orother anchoring devices, such as tacks, hooks, and pins, for thefixation of the implant to the patient's tissues. The three-dimensionalimplants can also incorporate sutures, with or without needles, for thefixation of the implant to the patient's tissues. These tabs and suturescan be placed in order to improve the implant's ability to contour tothe host's tissue, or to form an anatomical shape. In particular, thesetabs and sutures can be incorporated with appropriate spacing into theimplant so that they prevent migration of the implant. The tabs andsutures can also be incorporated to prevent the implant from bunching,kinking, folding or wrinkling.

In another embodiment, the three-dimensional implants can beself-anchoring. Preferably, the three-dimensional self-anchoringimplants incorporate a self-fixating system on the side of the implantthat contacts with the patient's tissue. The three-dimensionalself-anchoring implants can be made, for example, from a textile orfilm, such as a self-anchoring knitted or woven mesh. In an embodiment,a self-anchoring textile can be prepared, for example, with barbs,fleece, or self-fixating tips, or with micro grips. In one embodiment, aself-anchoring mesh may be prepared by shaving half loops from a loopedknitted mesh on the anchoring side of a three-dimensional implant. Inanother embodiment, a self-anchoring mesh may be prepared from more thanone fiber by inserting loops of heavier stiffer fiber during theknitting process or stitching loops into a pre-formed mesh, and thenshaving those loops to form barb like surfaces. In a further embodiment,self-anchoring three-dimensional implants may be prepared using a laserto cut the anchoring side of the implant to provide a plurality oftissue engaging barbs. In a preferred embodiment, the self-anchoringthree-dimensional implants are made from poly-4-hydroxybutyrate, andmore preferably from monofilaments thereof. In an even more preferredembodiment, the self-anchoring three-dimensional implants are made froma poly-4-hydroxybutyrate knitted mesh wherein the self-anchoring side ofthe mesh has been treated to form barbs, fleece, self-fixating tips, ormicro grips, for example, by shaving half loops or cutting with a laseror mechanical instrument.

The three-dimensional implants may be sterilized using ethylene oxide,gamma-irradiation, or electron beam radiation (e-beam). In a preferredembodiment, P4HB implants are sterilized using ethylene oxide, andpackaged.

IV. Methods of Delivery of Three-Dimensional PHA Implants

In a preferred embodiment, the implants described herein that can assumea three-dimensional shape unaided after being temporarily deformed areimplanted using minimally invasive techniques. These implants may, forexample, be rolled up into a small cylindrical shape, placed inside atubular inserter, and implanted through a small incision. Once releasedin vivo, these implants will assume their three-dimensional shapesunaided, and may be moved into position, for example, to contour to thehost's tissue (or form an anatomical shape) for use in hernia repair ortissue reinforcement. In a preferred embodiment, the implants aredesigned so that they will stretch in both directions to accommodate andreinforce tissue defects. The three-dimensional implants may alsoincorporate one or more medical markers to aid the surgeon inorientation of the implant.

One skilled in the art will appreciate that these three-dimensionalimplants can also be delivered by other minimally invasive methods aswell as using more traditional open surgery techniques.

The present invention will be further understood by reference to thefollowing non-limiting examples.

Example 1: Preparation of P4HB Monofilament by Melt Extrusion

Bulk P4HB resin in pellet form was dried to less than 300 ppm waterusing a rotary vane vacuum pump system. The dried resin was transferredto an extruder feed hopper with nitrogen purge to keep the pellets dry.The pellets were gravity fed into a chilled feeder section andintroduced into the extruder barrel, which was 1.50 inches in diameterand fitted with an extrusion screw with a 30:1 L/D ratio. The extruderbarrel contained 5 heating zones (or extrusion zones)—zones 1, 2, 3, 4and 5, and was manufactured by American Kuhne. The heated and softenedresin from the extruder was fed into a heated metering pump (melt pump)and from the melt pump the extruded resin was fed into the heated blockand an eight hole spinneret assembly. Processing profile ranges from 40°C. to 260° C. for temperatures, and 400 psi to 2000 psi for pressures,were used. The molten filaments were water quenched and conveyed into athree-stage orientation, with inline relaxation, before winding of themonofilaments on spools. Test values for extruded monofilament fiber areshown in Table 1.

TABLE 1 Mechanical Test Data for P4HB Monofilament Fiber Fiber USPDiameter, Breaking Break Size mm Strength, Kg Elongation 5/0 0.150 1.8030% 6/0 0.100 1.00 29%

Example 2: Preparation of a P4HB Monofilament Mesh

Spools with P4HB monofilament fiber prepared as described in Example 1were converted into P4HB monofilament mesh as follows: Monofilamentfibers from 49 spools were mounted on a creel, aligned side by side andpulled under uniform tension to the upper surface of a “kiss” roller.The “kiss” roller was spinning while semi-immersed in a bath filled witha 10% solution of TWEEN® 20 lubricant. The TWEEN® 20 lubricant wasdeposited on the surface of the sheet of fiber. Following theapplication of TWEEN® 20, the sheet of fiber was passed into a combguide and then wound on a warp beam. A warp is a large wide cylinderonto which individual fibers are wound in parallel to provide a sheet offibers. Next, warp beams were converted into a finished mesh fabric bymeans of interlocking knit loops. Eight warp beams were mounted inparallel onto tricot machine let-offs and fed into the knitting elementsat a constant rate determined by the ‘runner length’. Each individualmonofilament fiber from each beam was fed through a series of dynamictension elements down into the knitting ‘guides’. Each fiber was passedthrough a single guide, which was fixed to a guide bar. The guide bardirected the fibers around the needles forming the mesh fabricstructure. The mesh fabric was then pulled off the needles by the takedown rollers at a constant rate of speed determined by the fabric‘quality’. The mesh fabric was then taken up and wound onto a roll readyfor scoring.

Example 3: Scouring of P4HB Monofilament Mesh and Cytotoxicity Testing

The P4HB monofilament mesh produced according to the method of Example 2was scored ultrasonically with water, heat set in hot water, and thenwashed with a 70% aqueous ethanol solution. Cytotoxicity testing of twograms of the mesh was undertaken using the ISO Elution Method (1×MEMExtract) following the guidelines of the International Organization forStandardization 10993: Biological Evaluation of Medical Devices, Part 5:Tests for Cytotoxicity: in vitro Methods. The scoured P4HB monofilamentmesh passed the cytotoxicity testing.

Example 4: Preparation of a P4HB Implant from an Absorbable MonofilamentMesh that Unaided Assumes a Three-Dimensional Shape Designed to Contourto a Patient's Tissue for Hernia Repair

A split metal mold (see FIG. 1) consisting of an inwardly curving halfand a mating outwardly curving half, with a semicircular groove placedin the outlying border of the inwardly curving half was prepared. A P4HBmonofilament extrudate was extruded, cut to length, and pushed into thesemicircular groove with part of the monofilament protruding from thegroove. A knitted P4HB monofilament mesh, measuring approx. 15×20 cm,with a pore diameter of approximately 500 μm, thickness of 0.5 mm, arealdensity of approx. 182 g/m², suture pullout strength of 5.6 kgf, and aburst strength of 24.5 Kg, was draped over the entire surface of theinwardly curving half of the metal form and the monofilament in thesemicircular groove. The mating outwardly curving metal form was gentlyplaced over the mesh, and the two halves of the split metal mold wereclamped together to form a block. The block was uniformly heated on allsides by placing the block in hot water maintained at 56° C. for 5minutes. The block was then uniformly cooled for 1 to 2 minutes byplacing the block into a water bath at ambient temperature. The blockwas disassembled, and the three-dimensional mesh gently lifted from themetal mold. Unwanted compressed extrudate was removed from the implantby trimming the outlying border.

Example 5: Minimally Invasive Delivery of a Three-Dimensional P4HBImplant

The three-dimensional implant prepared in Example 4 was rolled into asmall diameter cylinder, and placed inside an insertion device suitablefor deployment of the implant in vivo.

The implant immediately assumed its three-dimensional shape unaided whenthe implant was deployed from the insertion device.

Example 6: Preparation of a P4HB Implant with an Absorbable MonofilamentMesh with a Three-Dimensional Shape without a Reinforced Outlying Borderfor Comparison with Example 4

A split metal mold (see FIG. 1) consisting of an inwardly curving halfand a mating outwardly curving half was prepared, but without asemicircular groove placed in the outlying border of the inwardlycurving half was prepared. A knitted P4HB monofilament mesh, measuringapprox. 15×20 cm, with a pore diameter of approximately 500 μm,thickness of 0.5 mm, areal density of approx. 182 g/m², suture pulloutstrength of 5.6 kgf, and a burst strength of 24.5 Kg, was draped overthe entire surface of inwardly curving half of the metal form. Themating outwardly curving metal form was gently placed over the mesh, andthe two halves of the split metal mold were clamped together to form ablock. The block was uniformly heated on all sides by placing the blockin hot water maintained at 56° C. for 5 minutes. The block was thenuniformly cooled for 1 to 2 minutes by placing the block into a waterbath at ambient temperature. The block was disassembled, and thethree-dimensional mesh gently lifted from the metal mold. Unwanted meshwas removed from the implant by trimming.

Example 7: Attempted Minimally Invasive Delivery of a Three-DimensionalP4HB Implant without a Reinforced Outlying Border for Comparison withExample 5

The implant prepared in Example 6 was rolled into a small diametercylinder, and placed inside an insertion device suitable for deploymentof the implant in vivo.

The implant failed to assume its three-dimensional shape unaided whenthe implant was deployed from the insertion device. This exampledemonstrates the need to reinforce the outlying border of athree-dimensional P4HB implant in order for the implant to assume itsoriginal shape unaided after being temporarily deformed.

Modifications and variations of the invention described herein will beobvious to those skilled in the art and are intended to come within thescope of the appended claims.

1-33. (canceled)
 34. A porous implant comprising a self-fixating system,wherein the implant further comprises poly-4-hydroxybutyrate orcopolymer thereof, and wherein the self-fixating system comprises atextile.
 35. The implant of claim 34, wherein the textile is a mesh,monofilament mesh, multifilament mesh, woven mesh, knitted mesh, braidor mesh comprising a barbed suture.
 36. The implant of claim 35, whereinthe textile further comprises one or more of the following: barbs,fleece, micro grips, hooks, anchoring devices, and self-fixating tips.37. The implant of claim 34, wherein the textile has a self-fixatingsystem on one side of the textile or both sides of the textile.
 38. Theimplant of claim 35, wherein the mesh is a looped knitted mesh and loopsof the mesh have been shaved or cut on one side of the mesh to form theself-fixating system on one side of the mesh, or the loops of the meshhave been shaved or cut on both sides of the mesh to form aself-fixating system on both sides of the mesh.
 39. The implant of claim38, wherein the loops of the mesh are cut to form a plurality of tissueengaging barbs.
 40. The implant of claim 35, wherein the mesh is formedwith two or more fibers, and the self-fixating system is formed bycutting one of the fibers.
 41. The implant of claim 40, wherein the meshis formed from two or more fibers, wherein one of the fibers is stifferthan the other fibers, wherein the stiffer fiber is incorporated asloops in the mesh, and the stiffer fiber is cut to form theself-fixating system.
 42. The implant of claim 41, wherein the stifferfiber has been inserted into the mesh during fabrication of the mesh, orwherein the stiffer fiber has been inserted into the mesh after the meshhas been fabricated.
 43. The implant of claim 34, wherein the implant isused in tissue reinforcement, hernia repair, can be temporarily deformedand unaided assume its original shape after implantation, or is shapedto contour to a patient's anatomy.
 44. The implant of claim 34, whereinthe implant further comprises one or more of the following: plasticizer,nucleant, dye, medical marker, bioactive agent, therapeutic agent,diagnostic agent, prophylactic agent, contrast agent, radiopaque marker,radioactive substance, hyaluronic acid or derivative thereof, collagen,hydroxyapatite, or an absorbable polymer comprising one or more of thefollowing monomeric units: glycolic acid, lactic acid, trimethylenecarbonate, p-dioxanone, and caprolactone.
 45. The implant of claim 34,wherein the implant is packaged and sterilized using ethylene oxide,gamma-irradiation or electron beam radiation.
 46. A method of formingthe implant of claim 34, the method comprising the steps of: (a)preparing a textile by knitting monofilament fiber ofpoly-4-hydroxybutyrate or copolymer thereof into a mesh, and (b) cuttingfiber of the mesh to form a self-fixating system comprising a pluralityof tissue engaging barbs, fleece, micro grips, hooks, anchoring devices,and self-fixating tips.
 47. The method of claim 46, wherein the mesh isa looped knitted mesh, and the loops are shaved or cut to form theself-fixating system.
 48. The method of claim 46, wherein the mesh isknit from more than one fiber including at least one stiffer fiber, andwherein mesh loops formed from a stiffer fiber are shaved or cut to forma self-fixating system comprising a plurality of barbs.
 49. A method ofimplanting the implant of claim 34, wherein the self-fixating system isengaged in the patient's tissue to reinforce tissue.
 50. The method ofclaim 49, wherein the implant is used in the closure of a laparotomy, orto reinforce a hernia repair.